CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation.
CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation.
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DOI：
10.1084/jem.20070109
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发表时间：
2007-07-09
期刊：
影响因子：
--
通讯作者：
Leonard WJ
中科院分区：
文献类型：
--
作者：
Kim HP;Leonard WJ
调节性T细胞（T reg细胞）是限制免疫应答的CD 4 + T细胞群体。FoxP 3是这些细胞发育和功能的主控转录因子，但其调控机制尚不清楚。我们已经在FoxP 3第一个内含子中鉴定出一个T细胞受体响应增强子，该增强子依赖于与CpG岛重叠的环AMP反应元件结合蛋白（CREB）/激活转录因子（ATF）位点。这个岛的甲基化与CREB结合和FoxP 3表达负相关。有趣的是，诱导T reg细胞形成的转化生长因子-β降低了CpG岛的甲基化并增加了FoxP 3的表达。类似地，用5-氮杂胞苷抑制甲基化或敲低DNA甲基转移酶Dnmt 1也诱导FoxP 3表达。相反，CpG岛的甲基化降低CREB结合或显性阴性CREB的表达，从而降低FoxP 3基因表达。因此，T细胞受体诱导的FoxP 3在T reg细胞中的表达受到CREB/ATF的序列特异性结合和CpG岛的DNA甲基化的控制。
Regulatory T cells (T reg cells) are a population of CD4+ T cells that limit immune responses. FoxP3 is a master control transcription factor for development and function of these cells, but its regulation is poorly understood. We have identified a T cell receptor–responsive enhancer in the FoxP3 first intron that is dependent on a cyclic-AMP response element binding protein (CREB)/activating transcription factor (ATF) site overlapping a CpG island. Methylation of this island inversely correlates with CREB binding and FoxP3 expression. Interestingly, transforming growth factor-β, which induces T reg cell formation, decreases methylation of the CpG island and increases FoxP3 expression. Similarly, inhibiting methylation with 5-azacytidine or knocking down the DNA methyltransferase Dnmt1 also induces FoxP3 expression. Conversely, methylation of the CpG island, which decreases CREB binding or expression of dominant-negative CREB, decreases FoxP3 gene expression. Thus, T cell receptor–induced FoxP3 expression in T reg cells is controlled both by sequence-specific binding of CREB/ATF and by DNA methylation of a CpG island.
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